Studies from this laboratory by Fishman et al (Science 204:1089,1979) have reported that women at familial high risk for breast cancer have an abnormal pattern of urinary estrogen excretion: whereas low-risk women show a marked rise of the excretion of estradiol glucuronide and estrone glucuronide during the periovulatory and luteal phases, high-risk women show less rise above follicular excretion levels, so that a significant difference in estrogen glucuronide excretion between the two groups appears during the later phases that is not present during the earlier phase. To explain these findings, it was postulated that high-risk women have an innately limited capacity to form glucuronide conjugates of estrogens, and that this capacity is exceeded during the periovulatory and luteal phases when the estradiol secretion rate rises sharply above the baseline follicular level. The objective of the present study is to compare the estradiol-glucuronidating capacity of high-risk and low risk women directly by measuring the steady-state urinary excretion of estradiol glucuronide that is achieved during a six-hour, constant-load intravenous infusion of a supraphysiological amount of estradiol (500 ng/minute). If deficient glucuronidating capacity is demonstrated in high-risk women as a group, this measure could be applied, in a later study, to the investigation of multiple members of high-risk kindreds, in order to determine the risk status of individuals and to establish the pattern of inheritance of risk.